Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): Molecular genetics, clinical experience, and fetal morphology

Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common hereditary renal cystic diseases and has a high infant mortality. Prenatal diagnosis using fetal sonography can be unreliable, especially in early pregnancy. The ARPKD locus has been mapped to proximal chromosome 6p allowing haplotype‐based prenatal diagnosis in “at‐risk” families. From December 1994 to March 1997, we received 258 inquiries regarding prenatal evaluation and we have completed analyses in 212 families. To date, 65 prenatal analyses have been performed in 57 families. In the majority of the requesting families (45/57), the index children are deceased and their DNA was extracted from paraffin‐embedded tissue. Eighteen fetuses were homozygous for the disease‐associated haplotypes. In 12 of these fetuses, pathoanatomical examination demonstrated typical ARPKD changes consisting of dilated collecting ducts and the characteristic hepatic ductal plate malformation. These changes were detected in two fetuses as early as 13 weeks gestational age. These cases represent the earliest demonstration of ARPKD‐associated histopathology reported to date. One high risk fetus was carried to term and turned out to be unaffected. However, the diagnosis of ARPKD remained doubtful in the index patient. Forty‐three fetuses were either heterozygous or homozygous for a nondisease‐associated haplotype and all infants born were phenotypically unaffected at birth. In four cases, a recombination event occurred between the flanking markers and no genotypic prediction was possible. Three of these pregnancies were terminated and necropsy of the fetuses confirmed ARPKD, while one fetus was carried to term and showed no abnormalities at birth. These results show that haplotype‐based prenatal testing is feasible and reliable in pregnancies “at risk” for ARPKD. An absolute prerequisite for these studies is an accurate diagnosis of ARPKD in previously affected sib(s). Am. J. Med. Genet. 76:137–144, 1998. © 1998 Wiley‐Liss, Inc.